Diffuse large B-cell lymphoma
Description
- Commonest lymphoma - ~30-40% of all NHL. Aggressive but curable
- Rapidly enlarging nodal or extranodal mass +/- B symptoms
- Extranodal in ~40%: GI (commonest), Waldeyer's ring, bone, testis, CNS, breast, skin
- De novo, or transformed from an indolent lymphoma ("Richter" from CLL, transformed follicular)
WHO-5 / ICC entities to separate out
- DLBCL NOS - the bulk; subdivided by cell of origin
- High-grade B-cell lymphoma with MYC and BCL2 rearrangement ("double-hit")
- BCL6 double-hit no longer part of the definition in WHO-5
- Primary mediastinal B-cell lymphoma - young F, bulky mediastinum, distinct biology/treatment
- Primary CNS lymphoma, primary testicular, intravascular, EBV+ DLBCL
- T-cell/histiocyte-rich large B-cell lymphoma
Epidemiology
- ~7/100,000/yr; >2,000 new cases/yr Australia
- Median age ~65-70; M>F slightly
- Incidence rises steeply with age; increasing overall (ageing, better ascertainment)
Aetiopathogenesis
- Malignant transformation of a mature germinal-centre or post-germinal-centre B cell
Cell of origin (Hans algorithm / gene expression)
| Marker pattern | Biology | |
|---|---|---|
| GCB (~60%) | CD10+ or BCL6+/MUM1- | EZH2, BCL2 translocation, better prognosis |
| ABC / non-GCB (~40%) | CD10-, MUM1+ | Constitutive NF-kB (MYD88 L265P, CD79B), worse prognosis |
- MYC rearrangement ~10%; with BCL2 = double-hit, high-grade B-cell lymphoma, poor outcome
- "Double-expressor" (MYC + BCL2 protein by IHC, no translocation) is also adverse but a different entity
- Risk factors: immunosuppression (HIV, post-transplant/PTLD, methotrexate, TNF inhibitors), autoimmune disease (Sjogren, RA, coeliac), EBV, HCV, HHV-8, prior indolent lymphoma
Diagnosis
Tissue
- *Excisional or generous core biopsy - FNA is inadequate*, architecture is required
- Sheets of large cells effacing architecture; high Ki-67 (typically 60-90%)
- IHC: CD20, CD79a, PAX5; CD10/BCL6/MUM1 for cell of origin; MYC and BCL2 protein
- FISH for MYC in all; if MYC rearranged, BCL2 (+/- BCL6) - defines high-grade B-cell lymphoma
- EBER if immunosuppressed or elderly
Staging
- PET-CT (FDG-avid) - Lugano staging; PET replaces marrow biopsy in most
- Marrow biopsy still if PET negative and cytopenias, or discordant low-grade involvement suspected
- CSF cytology + flow if CNS risk
- Bloods: LDH, FBE, UEC, LFT, urate, beta-2 microglobulin, HIV/HBV/HCV serology (HBV reactivation with rituximab)
- Baseline echo (LVEF) before anthracycline; hepatitis B core antibody status
IPI - "APLES", 1 point each
| Adverse | |
|---|---|
| Age | >60 |
| Performance status | ECOG >=2 |
| LDH | > upper limit normal |
| Extranodal sites | >=2 |
| Stage | III-IV |
- 0-1 low, 2 low-intermediate, 3 high-intermediate, 4-5 high
- NCCN-IPI refines with age and LDH as continuous variables and specific extranodal sites
CNS-IPI
- IPI factors + renal or adrenal involvement
- 4-6 points = high risk (~10%) -> CNS-directed prophylaxis or surveillance
- Testis, breast and epidural involvement are high risk regardless of score
Management
Curative intent in nearly all - fitness, not age alone, determines the regimen.
A. First line - advanced or high-risk disease
| Regimen | Indication |
|---|---|
| Pola-R-CHP x6 | IPI >=2 - polatuzumab vedotin (anti-CD79b ADC) replaces vincristine. POLARIX: improved PFS, no OS difference |
| R-CHOP x6 | Standard alternative; still appropriate for low-risk and for GCB disease |
| R-mini-CHOP | Elderly/frail. Do not omit the anthracycline if cure is intended |
| DA-EPOCH-R | High-grade B-cell lymphoma (double-hit), primary mediastinal, HIV-associated |
- CHOP = cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine), prednisone
- R-CHOP x3-4 + involved-site RT (or x4 alone if PET-negative) for limited-stage low-risk disease (FLYER, S1001)
- Interim PET is not used to change therapy outside trials; end-of-treatment PET (Deauville) defines response
B. Supportive care - built into every cycle
- G-CSF prophylaxis - febrile neutropenia risk highest days 7-11
- Tumour lysis prophylaxis - hydration + allopurinol; rasburicase if bulky, high LDH or renal impairment
- HBV antiviral prophylaxis if HBsAg+ or anti-HBc+ - rituximab causes fatal reactivation
- PJP prophylaxis; not routine unless steroid-heavy or HIV
- CNS prophylaxis - high CNS-IPI, testicular or high-risk extranodal: high-dose IV methotrexate (intrathecal alone insufficient)
- Fertility preservation before starting
C. Treatment toxicity to counsel for
- Anthracycline cardiotoxicity - baseline echo, require LVEF >50%; cumulative dose limit
- Vincristine - sensory peripheral neuropathy, constipation/ileus. Fatal if given intrathecally
- Polatuzumab - neuropathy, cytopenias (so vincristine is omitted, not added to)
- Alopecia, mucositis, infertility, secondary MDS/AML
D. Relapsed / refractory - stratify by timing
- *Time to relapse is the single most important variable*
| Timing | Approach |
|---|---|
| Primary refractory or relapse <12 months | CD19 CAR-T second line (axicabtagene ciloleucel, lisocabtagene maraleucel) - superior to salvage chemo/ASCT (ZUMA-7, TRANSFORM) |
| Relapse >12 months, transplant-fit | Salvage chemo (R-DHAP, R-ICE, R-GDP) -> autologous SCT if chemosensitive |
| Transplant- and CAR-T-ineligible | Bispecifics (glofitamab, epcoritamab), tafasitamab-lenalidomide, polatuzumab-BR, loncastuximab |
- CAR-T toxicity: CRS (tocilizumab +/- steroid), ICANS (steroid), prolonged cytopenias, hypogammaglobulinaemia
- Bispecifics: step-up dosing to limit CRS; off-the-shelf, no manufacturing delay
- Palliative RT for local symptoms
Associations
- HIV - and DLBCL is an AIDS-defining illness
- Post-transplant lymphoproliferative disorder (EBV-driven)
- Sjogren syndrome, RA, coeliac disease, Hashimoto thyroiditis
- Transformation from follicular lymphoma, CLL (Richter), marginal zone, Waldenstrom
- HCV, HBV, HHV-8 (primary effusion lymphoma)
- Chronic inflammation - pyothorax, breast implant, chronic osteomyelitis
- Common variable immunodeficiency, ataxia telangiectasia, Wiskott-Aldrich
Natural history & complications
- Curable: ~60-70% long-term disease-free with first-line immunochemotherapy
- Most relapses occur within 2 years - after 2 years relapse-free the risk falls sharply
- 5-yr OS by IPI: low ~90%, high ~50%
- Second-line CAR-T cures a substantial fraction of early relapses that were previously fatal
Adverse markers
- High IPI/NCCN-IPI, double-hit (MYC + BCL2 rearranged), ABC cell of origin
- Bulky disease (>7.5-10 cm), high LDH, primary refractory disease
- Positive end-of-treatment PET
Complications
- CNS relapse - ~5%, median survival months (the reason CNS-IPI matters)
- Tumour lysis, SVC obstruction, cord compression, GI perforation on treatment of gastric/bowel disease
- Late: cardiomyopathy, secondary MDS/AML, second solid cancers, infertility, hypogammaglobulinaemia
Surveillance
- Clinical review, not routine surveillance imaging - most relapses are symptomatic and scanning does not improve survival
- Cardiac and second-cancer surveillance long term
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